FoxP3 is well-established as the “master gene” that regulates the development and function of CD4+CD25+ T regulatory (Treg) cells. Generally, Treg cells represent approximately 5% of the CD4+ T-cells in human blood and are essential in maintaining immune homeostasis via Treg cell-mediated immune suppression, which may lead to tumor immune escape.
The immune system is subject to many levels of control which, together, avert attack on self tissues and limit over-exuberant immune responses to pathogens. In recent years, it has been recognized that distinct populations of T cells with ‘regulatory’ (or suppressor) function make a major contribution to keeping the immune system in check (1, 2). Amongst these, the best understood is the population of regulatory T cells characterized by constitutive expression of CD25 and the transcription factor FoxP3 (3, 4). These cells, known as Treg, are primarily noted for their ability to block the proliferation and cytokine secretion capacity of other T cells. Suppression is dependent on direct contact with the target cell yet, despite extensive investigation, the primary suppressive mechanisms involved are still unclear. Production of immunosuppressive cytokines such as TGF-β and expression of surface molecules such as CTLA-4 may play a role, but their relative importance remains controversial (5).
Despite an essential role in preventing autoimmunity, Treg can also have a negative impact on health by down-regulating beneficial immune responses such as those mounted against tumors. Numerous studies in animal models have demonstrated that specifically removing or inhibiting Treg dramatically improves tumor clearance and survival (6, 7). Furthermore, a number of reports have documented the presence of Treg within human tumor tissue, and in one of these studies the number of Treg also showed a clear negative correlation with survival (6-10). Thus, Treg may play a major role in preventing the development of effective anti-tumor immunity.
FoxP3 is a member of the forkhead family of transcription factors and, at least in mice, appears to act as a ‘master switch’ for the development and function of Treg (4, 11). Mice lacking functional expression of FoxP3 completely lack Treg, a deficit which is thought to be responsible for the fatal immunoproliferative disease these mice develop. Moreover, ectopic expression of FoxP3 in conventional mouse T cells endows them with the full phenotype and function of Treg. In humans, there is also a strong association between FoxP3 expression and the Treg phenotype, although the relationship may not be as simple as in mice (11). Mutations in FOXP3 have been associated with the development of a multi-organ autoimmune disorder known as IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) (12), suggesting that defects in FoxP3 expression or function lead to impaired Treg development. In keeping with this hypothesis, Treg from these patients have greatly reduced suppressive activity (13). Furthermore, ectopic expression of FoxP3 allows conventional human T cells to acquire many characteristics of Treg, although some studies have shown that their suppressive activity is inferior to that of bona fide Treg (14, 15). Interestingly, while expression of FoxP3 in freshly isolated peripheral blood is limited to Treg, in vitro activation can lead to a transient expression of FoxP3 by conventional T cells; it is currently a matter of debate as to whether or not these cells have regulatory activity (16-18). Thus, whereas FoxP3 is both necessary and sufficient for Treg activity in mice, other factors in addition to FoxP3 may be involved in induction of human Treg activity.